Project summary. The placenta sheds a vast amount of ?foreign? protein into maternal circulation during pregnancy, to be taken up and presented by maternal antigen presenting cells (APCs). Remarkably, the ensuing T cell response is neither immunogenic nor tolerogenic as pregnant mice neither become immunized to the antigen (Ag), even when given strong adjuvants and depleted of regulatory T cells, nor do they become tolerized to it. Thus, placental Ag is best considered ?non-immunogenic,? a potentially unique category without clear physiological antecedent. The objectives of this proposal are to elucidate the cellular and molecular basis for why placental Ag is non-immunogenic. This question is central to understanding how the placenta and fetus avoid immune rejection, and is also relevant to peripheral immune tolerance in general. As such it aligns perfectly with the long-term goal of Dr. Rizzuto which is to understand the immune pathogenesis of pregnancy complications and develop new therapies for use in transplantation, tumor immunology, and autoimmunity. The overall hypothesis of the proposal is that the non-immunogenicity of placental Ag can be explained by its physical/biochemical properties and/or the phenotype of the maternal APC, and has three specific aims. In Aim 1, Dr. Rizzuto will investigate the Ag presentation pathways governing CD4+ T cell responses and determine why these are non-immunogenic. This Aim builds upon preliminary data that B cells rather than DCs are critical for presenting placental Ag to maternal CD4+ T cells. In Aim 2, she will define the physical/biochemical properties of placental Ag that render it non-immunogenic, including exploring the functional significance of her finding that the Ag accumulates maternal antibodies. In Aim 3, she will define the Ag cross-presentation pathways that govern CD8+ T cell responses and determine why these are non- immunogenic. This Aim focuses on the classical Batf3-dependent DC subset known to cross-present Ag, as well as a currently undefined, and atypical APC. This work is relevant to the mission of NIAID because it will significantly expand the understanding of peripheral immune tolerance mechanisms. Dr. Rizzuto is an MD PhD research fellow at the University of California, San Francisco. She completed graduate work in tumor immunology and clinical training in anatomic pathology and is applying for a Mentored Clinical Scientist Research Career Development Award (K08). Her training plan will foster the attainment of her goal of becoming an academic physician scientist. This plan includes mentorship by Dr. Adrian Erlebacher, a leading expert in the field of reproductive immunology; scientific and career advisory by a multidisciplinary committee that includes leaders in the fields of immune tolerance and placental biology; coursework in reproduction, proteomics, and biostatistics; attendance at meetings to foster collaboration; and career development activities. These activities will provide Dr. Rizzuto with the necessary skills to merge her immunology research with her growing clinical expertise in perinatal pathology.